AB0816 TREATMENT OF A PATIENT WITH SEVERE DIFFUSE SYSTEMIC SCLEROSIS (SSC) USING CD19-TARGETING CAR-T-CELLS
Authors: C. Bergmann, F. Müller, D. Jörg, D. M. H. Györfi, S. Völkl, M. Aigner, T. Harrer, N. Bayerl, A. Atzinger, J. Taubmann, S. Boeltz, J. Wacker, M. Uder, T. Kuwert, M. Andreas, G. Schett
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Several data suggest a role of B-cells in SSc-pathogenesis: disturbed B-cell homeostasis with expansion of naïve and decrease of memory B-cells (1), increased levels of B-cell stimulating factors [2] and anti-fibrotic effects of B-cell-depletion in murine fibrosis models [3]. Although first randomized controlled trials show promising effects of the CD20-targeting antibody rituximab (RTX) in SSc (4,5), the role of B-cell targeting treatments remains controversial. A possible explanation is the limited B-cell repertoire targeted by CD20-depleting antibodies that spare early B-cell precursors, which are particularly expanded in SSc, as well as plasmablasts responsible for autoantibody production. Hence, deeper and wider B-cell-depletion may be effective in SSc treatment. Recently, CD19-targeting CAR-T-cells, that are used to deeply deplete B-cells in refractory lymphoma and leukemia, showed remarkable effects in refractory systemic lupus erythematosus patients, suggesting the principle feasibility to intercept with autoimmune disease via CD19-targeting CAR-T-cells. <h3>Objectives</h3> To test the feasibility of treating severe SSc with CD19-targeting CAR-T-cells. Outcomes: B-cell -, absolute and relative CAR-T-cell counts, ANA-titer, SSc-specific antibodies, <sup>68</sup>Ga-FAPI-04-uptake, carpal MRI, EUSTAR activity index, mRSS, TJC, forced vital capacity (FVC), diffusion coefficient (DLCO). <h3>Methods</h3> This is a case study of compassionate use of CD19-targeting CAR-T-cells in a 60-year old male patient with severe, diffuse SSc (year of diagnosis 2020 (first non-Raynaud manifestation, mRSS 24 at baseline) with diffuse myocardial fibrosis, lung fibrosis, Raynaud´s phenomenon and carpal arthritis who previously failed several standard therapies including methotrexate and mycophenolate. CAR-T-cell-infusion was performed upon lymphodepletion with fludarabine (25 mg/m<sup>2</sup> on days -5, -4, -3) and cyclophosphamide (1g/m2 on day -3) in August 2020 as single infusion. Immunosuppressive treatment was stopped before. Main outcomes were assessed before baseline and three months after CAR-T-cell infusion. <h3>Results</h3> CAR-T-cells expanded remarkably and fast <i>in vivo</i> from day 3 (0.3 cells/μl; 0.1% CARs of CD3+ T cells) until day 9 (0.30.19 (1275/μl; 66,35% CARs of CD3+ T cells) and were measurable until day 51 after infusion. B-cells were completely depleted by day 7 and were not detectable until day 77. Serum-IgG levels endured above 600mg/dl. CAR-T-cell therapy was well tolerated without signs of cytokine release syndrome or cell-associated neurotoxicity syndrome. ANA titers (before baseline: 1:320) and SSc-specific antibodies (anti-RNAP III antibodies, antigen RP11) were no longer detectable three months after CAR-T-cell-infusion. In parallel, myocardial tracer uptake was reduced by 30% in <sup>68</sup>Ga-FAPI-04-PET-CT imaging, a novel imaging technique that allows the molecular assessment of fibroblast activation <i>in vivo.</i> The extent of lung fibrosis on CT scan and pulmonary function test parameters was stable or slightly improved. As analyzed by contrast supported hand-MRI, carpal arthritis improved three months after CAR-T-cell therapy. Consistently, tender joint counts improved from n=22 at baseline to n=3 at 3 months follow up. In addition, tendon friction rubs were no longer present consistent with reduction of EUSTAR activity index. Skin fibrosis showed a tendency of improvement after 3 months as analyzed by two independent assessors. <h3>Conclusion</h3> We show for the first time, that CAR-T-cell therapy can result in the fast loss of SSc-specific autoimmunity in a patient with severe, diffuse SSc and is paralleled by amelioration of clinical manifestations including skin- and heart-fibrosis and arthritis. Further studies with longer follow-up times and more patients will help to further characterize the role of CAR-T-cell therapy in SSc. <h3>References</h3> [1]Sato S, et al. Arthritis Rheum. 2004 [2]Brown M, et al. Immunol. 2019 [3]Yoshizaki A. J Dermatol. 2016 [4]Ebata S, et al. The Lancet Rheumatology. 2021 [5]Maher TM, et al. Lancet Respir Med. 2022 <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Christina Bergmann Speakers bureau: Boehringer-Ingelheim, Pfizer, Grant/research support from: Boehringer-Ingelheim, Fabian Müller: None declared, Distler Jörg Consultant of: JHWD has consultancy relationships with Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Medac, Novartis, Pfizer, RuiYi and UCB, Grant/research support from: JHWD has received research funding from Anamar, Active Biotech, Array Biopharma, ARXX, aTyr, AstraZeneca, BMS, Bayer Pharma, Boehringer Ingelheim, Cantargia, Celgene, CSL Behring, Galapagos, GSK, Inventiva, Kiniksa, Sanofi-Aventis, RedX, UCB, Dr. med. Hermina Györfi: None declared, Simon Völkl: None declared, Michael Aigner: None declared, Thomas Harrer: None declared, Nadine Bayerl: None declared, Armin Atzinger: None declared, Jule Taubmann: None declared, Sebastian Boeltz: None declared, Jochen Wacker: None declared, Michael Uder: None declared, Torsten Kuwert: None declared, Mackensen Andreas: None declared, Georg Schett: None declared.